AU2002323774B2 - New compounds for treating impotence - Google Patents
New compounds for treating impotence Download PDFInfo
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- AU2002323774B2 AU2002323774B2 AU2002323774A AU2002323774A AU2002323774B2 AU 2002323774 B2 AU2002323774 B2 AU 2002323774B2 AU 2002323774 A AU2002323774 A AU 2002323774A AU 2002323774 A AU2002323774 A AU 2002323774A AU 2002323774 B2 AU2002323774 B2 AU 2002323774B2
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- compound
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- formula
- ethoxy
- ylsulphonyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1, 6-Dihydro-7H-pyrazolo[4,3] pyrimidin-7-one compound for the treatment of impotence Technical Field This invention relates to new compounds for the treatment of impotence. In particular, the present invention relates to new compounds for the treatment of impotence, their preparation method and their use.
Background of the invention Sildenafil is a selective inhibitor of phosphodiesterase whose chemical name is ethoxy-3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-5- 0 yl)phenylsulphonyl]]-4-methylpiperazine. This compound and its preparation method as well as its use in treating cardiovascular diseases was disclosed in CN1057464A; CN1124926A disclosed the use of this compound in preparing medicine for treating erection dysfunction of male animals. CN1168376A disclosed a new method for preparing sildenafil. CN1246478A disclosed another method for preparing sildenafil. Although sildenafil is very effective on treating male erectile dysfunction, the compound has strong toxicity and side effects.
Summary of the invention The present invention provides a new selective inhibitor of phosphodiesterase, i.e. the compound of formula and its pharmaceutically acceptable salts or its steroisomers. Such compound has the structure of formula 2 N-SO 2
OCH
2 CH3 N C H 2
CH
2
CH
3 HN N
N
0 CH3 Wherein, Ri and R 2 may be the same or different, and independently be C 1 6 alkyl, and preferably methyl, more preferably, R 1 and R 2 are both in the cis-form ofpiperazine ring and are both methyl.
S005028398 1^ O Another object of the present invention is to provide a method for preparing the N, compound of formula There are some new intermediates involved in the synthetic route of the present S invention. Therefore, the invention also relates to intermediates for preparing compounds of formula c Still another object of the invention is to provide a pharmaceutical composition comprising the compound of formula as active component.
CI Another object of the invention is to provide the use of the compounds of formula for preparing medicine for the treatment of impotence diseases.
o1 According to the present invention, there are two substituted groups, RI and R 2 and two asymmetrical carbon atoms on piperazine ring of the compounds of formula R, and R 2 can be in cis- or trans- form of the piperazine ring. Therefore, the compounds of formula are presented as various stereoisomers. These isomers and their pharmaceutically acceptable salts are all in the scope of compounds of the present invention.
Preferably, the compound of the present invention is the compounds of formula (I) wherein RI and R 2 are in the cis-form, and most preferably is the compound wherein RI and R 2 are both methyl and in cis-form. Its chemical name is: 5-[[2-ethoxy-5-(cis-2,6dimethylpiperazin-4-ylsulphonyl)phenyl]] -1-methyl-3-n-propyl-7,6-dihydro-1 H-pyrazolo [4,3-d] pyrimidin-7-one, the compound of formula
HN
N-SO
2
/-OCH
2
CH
3 N
CH
2 CH2CH 3
CN
20 0 CH 3 005028398 The compound of formula of the present invention is not only effective for the treatment of impotence diseases, such as male erectile dysfunction, but also have such features as long-lasting medical effectiveness and lower toxicity.
The following shows a method of preparing the compound of formula which is a non-limiting example of preparing compound of formula The synthetic route of the compounds of formula of the present invention is illustrated as follows: 'COON, c 1 S07 SOc 12 GOOR HN C I SOSH
NO
bOk'CH OCH2CH3 0001 SOC 12 CocCI alI+NH-I
NH
2
H
3 0
CH
2
CIA
2
CH
3 ,(Ci- 3 :i- 2 3~
CH
2
CK
2 0H 3 05028398 N
CH
2
CH
2
CH
3
K/(CH
3 3
C-OH
HN N
NHN^N
O CH 3
I'
The compound of formula was prepared as follows: reacting 2-ethoxy benzoic acid as raw materials with chlorosulfonic acid in the presence of thionyl chloride, results in chlorosulphonyl-2-ethoxy benzoic acid (compound II); reacting compound II with cis-2,6dimethyl piperazine (see, Zhongguo Yiyao Gongye Zazhi, 1997, vol.28 page 524-525), results in 2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl) benzoic acid (compound III); acylation of compound (III), which is a new compound, obtained 2-ethoxy-5-(cis-2,6dimethylpiperazin-4-ylsulphonyl) benzoyl chloride (compound IV); reacting compound IV with compound V (see the synthesis method of the compound of formula IX in CN1246478A), in the presence of 4-dimethylaminopyridine and triethylamine, obtained 4-[[2-ethoxy-5-(cis-2,6dimethylpiperazin-4-ylsulphonyl)benzamido]]- mide(compound VI in the presence of potassium t-butoxide, obtained 5-[[2-ethoxy-5-(cis-2,6dimethylpiperazin-4-ylsulphonyl) phenyl]]-l-methyl-3-n-propyl-7,6-dihydro-lH-pyrazolo[4,3-d] pyrimidin-1-one (compound DETAILED DESCRIPTION OF THE INVENTION The method for preparing the compounds of formula of the present invention and their pharmaceutically acceptable salts is hereinafter described by examples. It should be understood that the examples of the preparation methods are only for the purpose of illustrating the present invention and the invention is not limited to the examples. Any modifications under the concept of the present invention to the preparation methods of the present invention all 05028398 belong to the scopes of the present invention.
O
S Example 1 Preparation of 5-chlorosulphonyl-2-ethoxy benzoid acid (II) In a 250ml three-neck flask, 2-ethoxy benzoic acid (50g, 0.30mol) was added dropwise to
INO
CI an ice-cooled mixtures of sulfoxide dichloride (22 ml, 0.30mol) and chlorosulfonic acid (82.6ml, 1.24mol) under stirring. At the same time, the temperature of the reacting mixture was kept below 25°C. the resulting mixture was stirred at room temperature for 18 hours and then poured S into ice water with stirring, and white deposit appeared. The reaction mixture was stirred for S another 1 hour and filtered, washed with water and dried in vacuum, gave 64.4g of crude product as white solid (II) (yield 81%) M.p. 108-110°C. The crude product was used directly in the next (N 10 step without further purification.
Example 2 Preparation of 2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl) benzoic acid (III) In 250ml three-neck flask, 52.6g(0.23mol) of cis-2, 6-dimethylpiperazine was added to the suspension of compound (II) (53g, 0.20mol) in water (170ml) at about 10°C with stirring, a the same time the temperature of reacting mixture was kept below 20 0 C. The reaction was then stirred at 100C for another 2 hours. The precipitate was filtered, ice-water washed, dried and refluxed in acetone for 1 hour, and purified, gave 48g compound (III) (yield 70%) as white crystalline, m.p. 260.5-273.0°C (Dec.) HNMR(DMSO) 5 7.72-7.75(2H, H-4 and H-6 on benzene ring), 7.26-7.28(1H, H-3 on benzene right), 4.12-4.17(2H, -CH 2 on -OCH 2
CH
3 3.53(2H, -CH 2 on piperazine ring), 2.89-2.92(2H, -CH- on piperazine ring), 1.80-1.86(2H,
-CH
2 on piperazine ring), 1.31-1.34(3H, -CH 3 on -OCH 2
CH
3 1.0-1.04(6H, -CH 3 on piperazine ring).
Example 3 Preparation of 2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl) benzoyl chloride(IV) Compound (III) (34.2g, 0.lmol) and sulfoxide dichloride (73.0ml, 0.5mol) was charged into a 250ml three-neck flask and the resulting mixture was heated under reflux for 3 hours. The unreacted sulfoxide dichloride was then evaporated under reduced pressure. The ethyl acetate was added into the residue, and stirred. The precipitate was filtered, washed with ethyl acetate, dried under vacuum, gave 29.4g compound (IV) as a yellow solid 206.0-209.5 0
C.
05028398 1-NMR(D 2 0) 6 :8.0(11-H, H-6 on benzene), 7.74-7.76(l1H, H-4 on benzene), 7.14-7.16(l1H, H-3 c1 on benzene), 4.08-4.1 1(2H, -CH 2 on -OCH 2 GHA) 3.74-3.77(2H, -CH 2 on piperazine ring), 3.32(2H, -CH- on piperazine ring), 2.19-2.25(2H, -CH 2 on piperazine ring), 1.24-1.27(3H, -CH 3 on -OCH 2 CHA) 1.09-1.1 0(6H, -CH 3 on piperazine ring).
Example 4 Preparation of 4-I-2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl) benzamidel-I-methyl-3-n-propyl In a 500m1 three-neck flask, I 25m1 of methylene chloride, 9.1 g(05mol) of 1 -methyl-4amino-3 -n-propyl pyrazole-5-formamnide 0.06g(0.0005mo1) of 4-dimethylaminopyridine and 10.1 g(0. Imol) of triethylamine were added successively and then the mixture was cooled to below I10 0 C. A solution of the compound (IV) (25.80g, 0.065mo1) in methylene chloride (I125m1) was added dropwise into the mixture and then stirred at this temperature for 2 hours. The solvent was evaporated, then water was added to the residue. The solid was filtered and washed with ethyl acetate, gave 19.2g compound (VI) as a grey-white solid m.p.197-198.5'C (yield HNMR(CDC1 3 5 8.62(1H, H-6 on benzene ring), 7.90-7.92(1H, H-4 on benzene ring), 7.90(1H, 7.17-7.27(1H, H-3 on benzene ring), 5.73(1H, -NH- on piperazine ring), 4.37-4.41(2H, -OCH 2
CH
3 4.06(3H, N-CH 3 3.63-3.66(2H, -CH 2 on piperazine ring), 3.0(2H, -CH- on piperazine ring), 2.52-2.56(2H, -CH 2
CH
2
CH
3 1.84-1.90(2H, -CH- on piperazine ring), 1.65-1.69(2H, -CH 2
CH
2
CH
3 1.58-1.63(3H, -OCH 2
CH
3 1.03-1.05(6H,
-CH
3 on piperazine ring), 0.94-0.97(3H, -CH 2
CH
2
CH
3 Example 5 Preparation of 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin- 4-ylsulphonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-lH-pyrazolo[4,3-d]pyri midin-7- one In a 250ml three-neck flask, 1.8g(0.046mol)of metallic potassium and 96ml of dry tert-butyl alcohol were added, then to the mixture 19g(0.0387mol) of compound (VI) was added. The mixture was heated to reflux with stirring for 8 hours, then cooled to room temperature. 96ml of water was added and the pH was adjusted to by adding 0.5mol/l of hydrochloric acid, giving precipitate and then standing for 1 hour at a temperature below 10°C. The precipitate was filtered, washed with ice-water, dried and gave 17.0g compound (yield 93%) as white crystalline. m.p.
202.2-203.2 HNMR(MeOD) 6 8.15(1H, H-6 on benzene ring), 7.90-7.93(1H, H-4 benzene ring), 7.36-7.38(1H, H-3 on benzene ring), 4.32(2H, -OCH 2
CH
3 4.23(3H, N-CH 3 3.75-3.78(2H, -CH 2 on piperazine ring), 3.10(2H, -CH- on piperazine ring), 2.86-2.89(2H, -CH 2
CH
2
CH
3 2.04-2.10(2H, -CH 2 on piperazine ring), 1.80-1.84(2H, -OCH 2
CH
2
CH
3 1.45-1.48(3H, -OCH 2
CH
3 1.14-1.17(6H,
-CH
3 on piperazine ring), 0.97-1.01(3H, -CH 2
CH
2
CH
3 If necessary, the compound of formula may be converted into its pharmaceutically acceptable salts by conventional method.
The inventors of the present invention discovered that the compound of the present invention is very effective for treating male erectile dysfunction diseases and has lower toxicity and side effects. Specific results ofpharmacodynamics and toxicity test are summarized as follows: Example 6 Pharmacodynamics test Test 1. Penis erection test of the compound formula in rats with testis removed The result indicates that the latent period of penis erection by electric irritation can be significantly shortened (P<0.05 and P<0.01) in rats administered the compound formula at the dosage of 24mg/kg and 12mg/kg, respectively. This result is the same as another compound sildenafil (P<0.01).
Test 2. Effect of the compound formula on the sexual function in mice with testis removed 004570374 Result a. The result shows that latent period which male mice catch female mice can be significantly shortened (P<0.05 and P<0.01) after administration of the compound of formula at the dosage of 24mg/kg and 12mg/kg, respectively.
Result b. The result shows that the times of back-climbing on female mice by male mice (times of sexual intercourse) can be significantly increased (P<0.05 and P<0.01) when the male mice was administrated the compound formula at the dosage of 24mg/kg and 12mg/kg, respectively.
Exampe 7 Toxicity test It was observed by using Bliss method that the half-lethal dosage (LDso) is 901.5mg/kg when mice were administrated the compound formula orally by gavage.
The confidence limit of 95% is 772.5-1052.1mg/kg.
According to the "Chinese Journal of Clinical Pharmacology and Therapeutics", 1999, 237-240, the LD 50 of the compound sidenafil is 625mg/kg when male mice were administrated orally in the single dose, and the confidence limit of 95% is 672mg/kg.
It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia or in any other country.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprising" and grammatical variations thereof, is used in the sense of "including" i.e. the features specified may be associated with further features in various embodiments of the invention.
Claims (7)
1. A compound of formula or a pharmaceutically acceptable salt or a stereoisomer thereof: -OCH 2 CH 3 Wherein, RI and R 2 may be the same or different and independently be C.-6 alkyl.
2. The compound according to claim 1, wherein said compound is 5-[[2-ethoxy-5-(cis-2,6- dimethylpiperazin-4-ylsulphonyl)phenyl -methyl-3-n-propy 1-7,6-dihydro- H- pyrazolo[4,3-d]pyrimidin-7-one, and said compound has the structure of formula as follows:
3. A method for preparing the compound of formula comprising the following steps: a. reacting 2-ethoxy benzoic acid, as raw materials, with chlorosulfonic acid in the presence of sulfoxide dichloride, obtaining 5-chlorosulphonyl-2-ethoxy benzoic acid (compound II); 05028398 COOH OCH- 2 CH 3 CIS0 2 COOH 4 CISO 3 H I OCH 2 CH 3 b. reacting the compound II with cis-2,6-dimethyl piperazine, obtaining (cis-2, 6-dimethyl piperazin-4-ylsulphonyl) benzoic acid (compound III); C'S02 HN 1 COOH NH OCH 2 CH 3 N"IS2d -HC3 III C. nucleophilicacyl substitution of the compound III, obtaining 2-ethoxy-5-(cis-2,6- dimethylpiperazin-4-ylsulphonyl)benzoylchloride(IV); SOC1 2 d. reacting the compound (IV) with the compound in the presence of 4- dimethylarninopyridine and triethylamine, obtaining 4-[2-ethoxy-5-(cis-2,6- dimethylpiperazin-4-ylsulphonyl)benzamido] -1-methyl-3 carboxamide (compound VI); HN- HI+ NH 2 CH 2 CH 2 CH 3 N 0 H1C v 004986250 e. cyclization of the compound VI in the presence of potassium t-butoxide, obtaining ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl)phenyl]]- I-methyl-3 -n-propyl-7,6-dihydro- IH-pyrazolo[4,3-d] pyrimidin-7-one (IF).
4. A compound of formula which is 4-[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4- ylsulphonyl)benzamido]-lI-methyl-3 -n-propyl-pyrazole-5-carboxamnide, having the structure as follows: VI 004986250 A pharmaceutical composition for treating impotence, comprising a therapeutically effective amount of a compound of formula its pharmaceutically acceptable salts or stereoisomers, as an active component, and a pharmaceutical acceptable carrier.
6. The pharmaceutical composition according to claim 5, wherein the compound of formula is 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulphonyl)phenyl]]-1-methyl-3-n-propyl- 7,6-dihydro-H-pyrazolo[4,3-d]pyrimidin-7-one.
7. A method of treating impotence diseases in a subject comprising administering to the subject a composition comprising a compound of formula
8. The method of claim 7, wherein the compound of formula is 5-[[2-ethoxy-5-(cis-2,6- dimethylpiperazin-4-ylsulphonyl)phenyl]]-l-methyl-3-n-propyl-7,6-dihydro- H-pyrazolo[4,3- d]pyrimidin-7-one. Dated 6 January 2006 Freehills Patent Trade Mark Attorneys Patent Trade Mark Attorneys for the Applicant: Baoshun Liu
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01129691 | 2001-06-29 | ||
| CN01129691.7 | 2001-06-29 | ||
| CN02100198.7 | 2002-01-18 | ||
| CN02100198A CN1127506C (en) | 2001-06-29 | 2002-01-18 | Compound for treating impotence |
| PCT/CN2002/000433 WO2003016313A1 (en) | 2001-06-29 | 2002-06-21 | New compounds for treating impotence |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002323774A1 AU2002323774A1 (en) | 2003-05-29 |
| AU2002323774B2 true AU2002323774B2 (en) | 2007-10-25 |
Family
ID=25740515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002323774A Expired AU2002323774B2 (en) | 2001-06-29 | 2002-06-21 | New compounds for treating impotence |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6960592B2 (en) |
| EP (1) | EP1400522B1 (en) |
| JP (1) | JP4469174B2 (en) |
| KR (1) | KR100878739B1 (en) |
| CN (1) | CN1127506C (en) |
| AU (1) | AU2002323774B2 (en) |
| BR (1) | BRPI0211025B8 (en) |
| CA (1) | CA2451990C (en) |
| CY (1) | CY1115687T1 (en) |
| DK (1) | DK1400522T3 (en) |
| ES (1) | ES2519441T3 (en) |
| IL (1) | IL159386A0 (en) |
| MA (1) | MA26117A1 (en) |
| MX (1) | MXPA03011929A (en) |
| NZ (1) | NZ530548A (en) |
| PT (1) | PT1400522E (en) |
| RU (1) | RU2279433C2 (en) |
| WO (1) | WO2003016313A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360531C (en) * | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Pyrazolopyrimidine compounds for prevention and cure of impotence and frigidity |
| EP2024369A4 (en) * | 2006-06-05 | 2010-10-27 | Matrix Lab Ltd | Novel process for the preparation of sildenafil citrate |
| CN101914100B (en) * | 2010-04-13 | 2013-01-30 | 漆又毛 | Benzenesulfonyl lupetazin derivative and preparation method thereof |
| CN101891747B (en) * | 2010-07-02 | 2012-04-25 | 张南 | Compound capable of inhibiting phosphodiesterase type 5 and preparation method |
| CN109970744A (en) * | 2019-04-10 | 2019-07-05 | 重庆康刻尔制药有限公司 | A kind of synthetic method of sildenafil citrate intermediate |
| CN112745323B (en) * | 2020-12-30 | 2021-10-29 | 北京悦康科创医药科技股份有限公司 | Citric acid alidenafil crystal form H and preparation method and application thereof |
| CN113350301B (en) * | 2021-06-03 | 2022-10-04 | 刘宝顺 | New compound traditional Chinese medicine honeyed pill for treating impotence |
| WO2023109513A1 (en) * | 2021-12-14 | 2023-06-22 | 真奥金银花药业有限公司 | Use of aildenafil or salt thereof in preparation of medicine for preventing or treating ischemic brain damage |
| KR102580664B1 (en) | 2023-01-25 | 2023-09-21 | (주)나인팩토리커뮤니케이션 | Composition for topical skin application for feeling of swelling and warmth to the male genital organ, and improving blood circulation |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250534A (en) * | 1990-06-20 | 1993-10-05 | Pfizer Inc. | Pyrazolopyrimidinone antianginal agents |
| GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| GB9301192D0 (en) * | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
| GB9612514D0 (en) * | 1996-06-14 | 1996-08-14 | Pfizer Ltd | Novel process |
| AU4501199A (en) * | 1998-06-03 | 1999-12-20 | Almirall Prodesfarma S.A. | 8-phenylxanthine derivatives and their use as phosphodiesterase inhibitors |
| ES2166270B1 (en) | 1999-07-27 | 2003-04-01 | Almirall Prodesfarma Sa | DERIVATIVES OF 8-PHENYL-6,9-DIHIDRO- (1,2,4,) TRIAZOLO (3,4-I) PURIN-5-ONA. |
-
2002
- 2002-01-18 CN CN02100198A patent/CN1127506C/en not_active Expired - Lifetime
- 2002-06-21 EP EP02754139.0A patent/EP1400522B1/en not_active Expired - Lifetime
- 2002-06-21 BR BRPI0211025A patent/BRPI0211025B8/en not_active IP Right Cessation
- 2002-06-21 JP JP2003521235A patent/JP4469174B2/en not_active Expired - Lifetime
- 2002-06-21 CA CA002451990A patent/CA2451990C/en not_active Expired - Lifetime
- 2002-06-21 WO PCT/CN2002/000433 patent/WO2003016313A1/en active IP Right Grant
- 2002-06-21 KR KR1020037016805A patent/KR100878739B1/en active IP Right Grant
- 2002-06-21 AU AU2002323774A patent/AU2002323774B2/en not_active Expired
- 2002-06-21 RU RU2004102513/04A patent/RU2279433C2/en active
- 2002-06-21 DK DK02754139.0T patent/DK1400522T3/en active
- 2002-06-21 ES ES02754139.0T patent/ES2519441T3/en not_active Expired - Lifetime
- 2002-06-21 MX MXPA03011929A patent/MXPA03011929A/en active IP Right Grant
- 2002-06-21 PT PT2754139T patent/PT1400522E/en unknown
- 2002-06-21 IL IL15938602A patent/IL159386A0/en active IP Right Grant
- 2002-06-21 NZ NZ530548A patent/NZ530548A/en not_active IP Right Cessation
-
2003
- 2003-12-16 US US10/736,732 patent/US6960592B2/en not_active Expired - Lifetime
- 2003-12-26 MA MA27465A patent/MA26117A1/en unknown
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- 2014-10-31 CY CY20141100900T patent/CY1115687T1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP4469174B2 (en) | 2010-05-26 |
| ES2519441T3 (en) | 2014-11-07 |
| MA26117A1 (en) | 2004-04-01 |
| BRPI0211025B1 (en) | 2016-03-01 |
| KR20040010779A (en) | 2004-01-31 |
| CN1393444A (en) | 2003-01-29 |
| BRPI0211025B8 (en) | 2021-05-25 |
| CA2451990A1 (en) | 2003-02-27 |
| WO2003016313A1 (en) | 2003-02-27 |
| RU2279433C2 (en) | 2006-07-10 |
| JP2005500381A (en) | 2005-01-06 |
| EP1400522A1 (en) | 2004-03-24 |
| KR100878739B1 (en) | 2009-01-14 |
| MXPA03011929A (en) | 2005-03-07 |
| PT1400522E (en) | 2014-10-30 |
| CN1127506C (en) | 2003-11-12 |
| IL159386A0 (en) | 2004-06-01 |
| EP1400522A4 (en) | 2006-04-05 |
| CY1115687T1 (en) | 2017-01-25 |
| BR0211025A (en) | 2004-10-19 |
| NZ530548A (en) | 2005-04-29 |
| DK1400522T3 (en) | 2014-11-10 |
| CA2451990C (en) | 2008-06-17 |
| US6960592B2 (en) | 2005-11-01 |
| EP1400522B1 (en) | 2014-08-06 |
| RU2004102513A (en) | 2005-03-27 |
| US20040152709A1 (en) | 2004-08-05 |
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Owner name: GUANGZHOU YOUCARE BIOPHARMACEATICS CO., LTD. Free format text: FORMER OWNER WAS: LIU, BAOSHUN |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |